1. Field of the Invention
The present invention relates to compositions employing 3'-azido-3'-deoxythymidine (hereinafter azidothymidine or AZT) and their use in the treatment of psoriasis.
2. Description of the Related Art
Psoriasis is a common skin disorder characterized by epidermal proliferation and dermal inflammation. The disease may present a number of clinical manifestations, generally related to the severity or stage of the outbreak. Clinically, patients afflicted with psoriasis exhibit symptoms ranging from mild localized inflammation or irritation to severe pruritic lesions. Moreover, acute manifestations of the disease can lead to additional severe problems such as psoriatic arthritis and exfoliative erythroderma.
Although first recognized more than two centuries ago, and afflicting about 2 persons in every 100, the pathogenesis of psoriasis remains speculative. Although many theories have been put forth, the clinical diversity of the disease along with a lack of good animal models have made a definitive characterization of the disease elusive. Recent research has suggested a complex etiology possibly involving the interaction of intrinsic cellular defects and environmental factors (see, e.g., Anderson et al. (1986), "Psoriasis," Chapter 7 in Pathogenesis of Skin Disease, eds. Thiers and Dobson, pp. 67-85). Some evidence suggests the disease is a heritable disorder, or perhaps secondary to a vertically transmitted retrovirus.
By studying defects characterized in epidermal and related cells, a proposed cascade of pathogenic events which attempts to account for most of the observations have been summarized by Anderson et al., supra. Defective cell membrane function and cyclic nucleotide regulation may in turn result in altered polyamine, proteinase or arachidonic acid transformations. These changes may cause the epidermis to be primed to be hyperproliferative and the dermal microvasculative to overrespond to injury. Once the psoriatic process is triggered, inflammatory mediators and the immume system may produce a "positive feedback" exacerbation until treatment or negative regulatory factors supervene. Genetic, retroviral and environmental influences may work at all these levels.
Unfortunately, psoriasis treatment protocols and agents have generally proved inadequate, particularly in the treatment of more serious forms of the disease. Antiinflammatory steroids have been used extensively in the treatment of all forms of psoriasis. For milder forms of the disease, topical steroid preparations and various surface-acting type agents such as mild irritants or antiseptics which may or may not have keratolytic properties, have been used. Examples of drugs employed as cutaneous surface-acting drugs in the treatment of psoriasis include substituted phenols such as cresol, tars, coal tars, miscellaneous topical germicides such as sulfur, ichthammol and anthralin.
For severe chronic or acute psoriasis, systematic administration of various antimetabolites and corticosteroids has generally been the treatment of choice. For example, methotrexate, a folic acid antagonist, is often employed in the treatment of more severe forms such as exfoliative psoriasis, generally in dose ranges of about 2.5 to 5.0 mg orally for five days, or 25 to 50 mg intravenously weekly. However, dose levels necessitated by a very severe case can lead to leukopenia and other potentially life threatening toxicities.
Other types of antimetabolites often employed in the treatment of psoriasis include both purine and pyrimidine analogs. For example, azaribine (triazure), a triacetyl derivative of azauridine, has been effective in the treatment of generalized psoriasis and polycythemia vera. It has been suggested that azaribine acts through the inhibition of pyrimidine biosynthesis in affected cells. Purine analogs such as azathioprine have also been employed in treating psoriasis. This drug may act through an immunomodulation mechanism in that it has also been employed to suppress the immune response, for example, in the prevention of the rejection phenomena in organ transplantation.
Existing protocols for the treatment of other autoimmune diseases such as vitiligo and lupus erythematosus has similarly been lacking, due in large part to the lack of knowledge concerning the etiology of such diseases. In general, many of the agents used in treating psoriasis have also been used in the treatment of other autoimmune diseases such as lupus. These include, for example, the above-mentioned cutaneous surface acting agents as well as corticosteroids, both topical and systemic. In vitiligo, agents such as methoxsalen and trioxalen are also employed to increase skin tolerance to sunlight and to facilitate repigmentation of the skin. Although the foregoing agents have found some use in the treatment of autoimmune disease, they clearly do not represent ideal treatment modalities.
Unfortunately, there has been up until now no clear drug of choice in the treatment of autoimmune disease, and particularly, for the treatment of severe exfoliative processes or highly pruritic lesions such as are seen in psoriasis. Without a clear understanding of the disease pathology, or a common structure-activity relationship separating useful from marginally or unuseful agents, specific drug design for anti-psoriatic agents has been thwarted. There is accordingly an urgent need to identify pharmaceutical agents useful in the treatment of psoriasis, and particular agents active in the more severe forms.